Diethyl Ether → HCID 86758650, compound

To methyl magnesiumbromide (3M solution in diethyl ether, 0.225 ml) in anhydrous diethyl ether (7 ml) under a nitrogen atmosphere was added slowly 4-[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]benzoyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.23 g, Example 76a) in anhydrous diethyl ether (7 ml). The reaction mixture was stirred for 14 h at room temperature, then poured onto crushed ice. A solution of 10% aqueous potassium hydrogen sulphate was added keeping the pH of the solution >4. The layers were separated, and the aqueous layer was extracted with ethyl acetate (4×25 ml). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in methanol (3 ml) and hydrochloric acid (4N solution in dioxane, 2 ml) and stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product (0.11 g) was redissolved in dichloromethane (3 ml). Triethylamine (0.066 ml) was added followed by di-tert-butyl-dicarbonate (0.055 g) and the reaction mixture was stirred for 1 hour at room temperature. Water was added and the layers were partitioned. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane, then by RPHPLC eluting with a gradient of 75-5% of 0.1% aqueous ammonium acetate in acetonitrile to give the subtitle compound as a white foam (0.06 g).

1. additionpoured
2. customonto crushed ice
3. customThe layers were separated
4. extractionthe aqueous layer was extracted with ethyl acetate (4×25 ml)
5. dry with materialdried over anhydrous magnesium sulfate
6. filtrationfiltered
7. concentrationconcentrated under reduced pressure
8. dissolutionThe residue was dissolved in methanol (3 ml)
9. stirringhydrochloric acid (4N solution in dioxane, 2 ml) and stirred for 14 h at room temperature
10. customSolvents were then removed under reduced pressure
11. dissolutionthe product (0.11 g) was redissolved in dichloromethane (3 ml)
12. additionTriethylamine (0.066 ml) was added
13. stirringthe reaction mixture was stirred for 1 hour at room temperature
14. additionWater was added
15. customthe layers were partitioned
16. extractionThe organic extract
17. dry with materialwas dried over anhydrous magnesium sulfate
18. filtrationfiltered
19. concentrationconcentrated under reduced pressure
20. customThe residue was purified by HPLC
21. washeluting with a gradient of 0-5% ethanol in dichloromethane
22. washby RPHPLC eluting with a gradient of 75-5% of 0.1% aqueous ammonium acetate in acetonitrile

ORD record

ord-c56166f631634070a7a1be207e8e5c80

Source dataset

uspto-grants-2002_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06492355B1